This study demonstrates that clonidine administration at doses which are standard for provocative GH testing is associated with respiratory depression defined as an oxygen saturation ≤94% and/or clinical signs of airway obstruction (e.g., sonorous respirations) in children with PWS. Clonidine consistently resulted in a reliable and moderate depth of sedation that was accompanied by small reductions in heart rate, respiratory rate, systolic blood pressure, and oxygen saturation. Five patients, on nine separate occasions, developed moderate reductions in oxygen saturation following clonidine administration. To our knowledge this is the first report to demonstrate respiratory depression in patients with PWS following a standard dose of clonidine used to assess GH secretion response. Collapsibility of the upper airway due to a depressed level of consciousness and loss of pharyngeal muscle tone is one of the most serious complications following sedative-anesthetic drug administration [28–30]. In this regard, clonidine is a sedative used in anesthetic practice and has potential to cause problems with upper airway tone. It is likely that respiratory control dysfunction in PWS patients, the respiratory depressant effects of clonidine, and the relatively high doses used to assess GH secretion create a heightened risk for respiratory depression in these children.
Numerous studies have demonstrated abnormal sleep patterns in patients with PWS that include hypoventilation, oxygen desaturation and sleep apnea [11–13, 31–36]. In addition to ventilation control abnormalities, children with PWS have additional risk factors that predispose them to abnormal pulmonary function and respiratory responsiveness. Hypotonia, obesity, and reduced muscle mass contribute to overall respiratory pump weakness and a restrictive lung pattern in patients with PWS . While none of our PWS patients were obese, abnormalities in body composition are already present during infancy , including reduced muscle mass, which may have contributed to the overall reduction in airway tone and ventilatory response following clonidine.
Recent reports of sudden death in children with PWS receiving GH supplementation have focused attention on the underlying respiratory disturbances in PWS. Our study was not designed to assess the effects of GH treatment on respiratory function on patients with PWS. Studies have demonstrated that pulmonary dysfunction directly contributes to mortality in the majority of PWS whether or not they are receiving GH [7–9]. Indeed, in a multicenter randomized controlled study no significant changes in sleep-related apneas or hypopneas were seen in young PWS patients receiving GH treatment . Tauber et al. found that 61% of sudden deaths in children with PWS were directly attributed to a respiratory problem . An upper respiratory infection was present in four of the nine episodes of oxygen desaturation in our study.
An intrinsic abnormality of respiratory drive in children with PWS could be exacerbated by the respiratory depressant effects of clonidine. Clonidine has few clinically significant respiratory depressant effects when used at doses of 3 to 4
g/kg [14, 16, 39–46]. In otherwise healthy adults declines in oxygen saturation were ≤1% following oral clonidine . Similarly, no oxygen saturations <95% were observed in children receiving 4
g/kg of oral clonidine as a preanesthetic medication . In fact, clonidine is considered so safe in this setting that few studies even discuss monitoring oxygen saturations following administration. Indeed only one study, adult patients without PWS, has demonstrated decreases in oxygen saturation that were accompanied by partial airway obstruction following clonidine as a preanesthetic medication . Of the nine oxygen desaturations in the children with PWS in our study, four were associated with partial airway obstruction.
The standard dose of clonidine to assess GH responsiveness is 0.15 mg/m2 [24, 25]. Interestingly, this dosing, based on surface area, resulted in a mean clonidine dose of 6.56
g/kg during the first study and 5.3
g/kg for all studies overall. Consequently clonidine doses were 1.5 to 2 times greater than typical doses used as a preanesthetic medication. To our knowledge use of pulse oximetry to assess respiratory function following clonidine for GH stimulation has not been studied. Yet, doses of clonidine for GH stimulation often exceed amounts identified in unintentional ingestions as potentially toxic . In a recent study examining clonidine ingestions in children, Spiller et al., recommended direct medical evaluation of all children 4 years of age and younger for clonidine ingestions of 0.1 mg and/or 5
g/kg or greater. Interestingly, of the 60 clonidine administrations in our study the average dose of clonidine exceeded 5
g/kg and 42 (70%) doses of clonidine were equal to or exceeded 0.1 mg or 5
g/kg. In patients experiencing low oxygen saturation five of the nine (55%) administrations exceeded 5
g/kg. While our setting and patient population is different than that described by Spiller et al., the recognition that doses of this amount have potential for serious adverse events in children is consistent with our findings in patients with PWS.
A limitation to our study was that it did not have the rigor of a blinded randomized controlled investigation. The lack of an alternative-treatment control group prevented us from being able to discern whether clonidine administration per se caused these respiratory abnormalities or was merely associated with them. We chose this design in order to assess a standard assessment tool. A randomized, placebo, controlled study will be necessary to clarify the respiratory effects of clonidine.
Secondly, detailed baseline sleep study information was not available for all patients. Since PWS patients often have sleep disordered breathing, the oxygen desaturation events in our 5 patients may simply represent what typically occurs in these patients during sleep. In addition, four oxygen desaturation episodes were in the presence of an upper respiratory tract infection. The presence of an upper respiratory infection may have exacerbated the respiratory dysfunction in this patient population following clonidine administration. Whether clonidine simply simulates what happens during normal sleep in PWS patients or accentuates an underlying respiratory control problem is unclear.
We used a definition of an oxygen desaturation of less than or equal to 94% as an adverse event. We chose to have a low threshold for reporting an oxygen desaturation in an effort to increase the sensitivity for detecting respiratory depression in our patient population. Our definition of an oxygen desaturation is similar to that used in other studies evaluating the safety of clonidine .
In conclusion, while the majority of patients with PWS developed only minimal respiratory changes following clonidine administration, a subset of patients experienced reductions in oxygen saturation that were accompanied by partial airway obstruction or shallow respirations. Further, clonidine doses used for GH stimulation in children are substantially greater than doses routinely used for sedation and in our patient population resulted in a moderate depth of sedation. The American Academy of Pediatrics recommends continuous monitoring of oxygen saturation and heart rate for all patients receiving moderate sedation . In our study all patients achieved a sedation level of 4 (drowsy, responds to mild stimulation) or 5 (asleep, does not respond to mild stimulation), following clonidine administration. This degree of sedation is consistent with the definition of moderate to deep sedation. Because of the large doses of clonidine used for GH stimulation and the intrinsic respiratory dysfunction in children with PWS we would recommend that all PWS patients receiving clonidine for GH stimulation receive continuous monitoring by pulse oximetry and be cared for by personnel proficient in the monitoring and management of the sedated pediatric patient. Further prospective studies are required to assess the risk of clonidine use in patients with PWS.